Synthesis of Benzothiophene-3-carboxylic Esters by Palladium Iodide-Catalyzed Oxidative Cyclization–Deprotection–Alkoxycarbonylation Sequence under Aerobic Conditions

A palladium-catalyzed carbonylative approach to benzothiophene-3-carboxylic esters, starting from simple and readily available building blocks [2-(methylthio)phenylacetylenes, CO, an alcohol, and O2 (from air)], is reported. The process is catalyzed by the simple PdI2/KI catalytic system to give the desired products in fair to high yields (57–83%). Interestingly, the reaction also works nicely in the ionic liquid BmimBF4 as the solvent, with the possibility to recycle the catalytic system several times without appreciable loss of activity.

The use of carbon monoxide as a C-1 building block for the direct synthesis of carbonylated heterocycles represents a major tool in current organic synthesis. 1 Among carbonylation processes, palladium(II)-catalyzed oxidative heterocyclization−alkoxycarbonylation reactions constitute a powerful methodology for the preparation of a variety of important heterocyclic derivatives starting from simple and readily available acyclic substrates. 2 In this field, in the course of the recent years, our group has contributed a number of examples, based on the successful use of a particularly simple catalytic system, consisting of palladium iodide in conjunction with an excess of potassium iodide ("PdI 2 /KI catalyst"). 3 A main characteristic of our system, besides avoiding the use of additional ligands or promoters apart from KI, is that it works very well with the simplest and most convenient oxidant possible, that is, oxygen (from air), without any need for other inorganic or organic oxidants (such as copper chloride or benzoquinone). 3 A possible limitation on the use of the PdI 2 /KI catalytic system in an oxidative S-heterocyclization−carbonylation process can be related to the well-known instability of sulfurbased nucleophiles (such as thiols) under aerobic conditions. Very recently, however, we have shown that it is possible to overcome this limitation by suitably "masking" the thiol group of the acyclic substrate by simple methylation. In fact, we found that 1-(methylthio)-3-yn-2-ols could be conveniently converted into thiophene-3-carboxylic esters by a sequence of steps involving 5-endo-dig S-cyclization, iodide-promoted demethylation, dehydrative alkoxycarbonylation, and Pd(0) aerobic reoxidation. 4 In this Note, we report a useful extension of this kind of reactivity to the use of readily available 2-(methylthio)phenylacetylenes, which allows synthesizing high-value-added benzothiophene-3-carboxylic esters 5 in a multicomponent fashion and using O 2 (from air) as the sole benign external oxidant. 6 On the basis of our previous results on PdI 2 /KI-catalyzed oxidative carbonylation of 1-(methylthio)-3-yn-2-ols to give thiophene-3-carboxylic esters, 4 in this work we have assessed the reactivity of 2-(methylthio)phenylacetylenes 1 (readily available by Sonogashira coupling between 2-halothioanisoles and terminal alkynes, as described in the Supporting Information) under similar conditions, with the aim of synthesizing benzothiophene-3-carboxylic esters 2. According to our mechanistic hypothesis, the formation of the desired products 2 can occur through an ordered sequence in steps involving the following: (a) triple bond coordination to the metal center; (b) 5-endo-dig S-cyclization, by intramolecular nucleophilic attack of the o-methythio group on the coordinated triple bond, to give sulfonium iodide intermediate I; (c) demethylation of I by the iodide anion, with formation of MeI and intermediate II; (d) reaction of MeI with water (initially present in the reaction mixture as an impurity and then also formed in the Pd(0) reoxidation step) with formation of MeOH and HI; (e) carbon monoxide insertion into the palladium−carbon bond of II to give III; (f) nucleophilic displacement by attack of an external alcohol ROH (either MeOH or a higher alcohol, used as the solvent) on III, to yield the benzothiophene-3-carboxylic ester 2, another 1 mol of HI, and Pd(0); (g) Pd(0) reoxidation to PdI 2 , through oxidation of 2 mol of HI by oxygen, to give water and I 2 , followed by oxidative addition of the latter to Pd(0) (Scheme 1; anionic iodide ligands are not shown for clarity).
To verify our work hypothesis, we first synthesized methyl(2-(phenylethynyl)phenyl)sulfane 1a (R = Ph) and used it as model substrate to optimize reaction conditions. The first reaction was carried out under conditions similar to those already successfully employed for the synthesis of thiophene-3carboxylates, 4 that are 5 mol % of PdI 2 in the presence of an excess of KI (5 equiv) in MeOH as the solvent and external nucleophile (R = Me) (substrate initial concentration, 0.02 mmol/mL of MeOH) at 80°C and under 40 atm of a 4:1 mixture of CO−air. After 15 h reaction time, substrate conversion (determined by isolation of unreacted 1a) was 91%, with formation of two carbonylation products: the desired methyl 2-phenylbenzo [b]thiophene-3-carboxylate 2a (43% isolated yield) and maleic diester 3a (7% GLC yield) derived from triple bond oxidative dialkoxycarbonylation 7 (Table S1, entry 1, Supporting Information).
To improve this initial result and make the process more selective toward 2a, we then carried out several experiments by changing the reaction conditions; the results obtained are shown and detailed in the Supporting Information (Table S1 and related text). Based on this brief reaction optimization study (see the Supporting Information), the best conditions for the selective formation of benzothiophene-3-carboxylate 2a are those of Table S1, entry 3. To further improve this product yield and achieve total substrate conversion, we then allowed the reaction to run under those conditions for 24 h instead of 15 h: gratifyingly, 2a could be isolated in 80% yield (Table 1, entry 1). 8 The process could also be carried out with lower catalyst loadings, as shown by the results reported in Table 1, entries 2 and 3 (a yield of ca. 60% of 2a was obtained with both 2.5 mol % and 1.7 mol % of PdI 2 ). Changing the reaction solvent and external nucleophile from MeOH to EtOH (R = Et) or i-PrOH (R = i-Pr) caused a slowdown of the reaction rate, so the process was carried out for 36 h rather than 24 h. The corresponding ethyl and isopropyl esters, however (2a′ and 2a′′, respectively), could be isolated in satisfactory yields (75% and 62%, respectively; Table 1, entries 4 and 5).
The method was then extended to other 2-(methylthio)phenylacetylenes, 1b−k, bearing different substituents R 1 on the triple bond and R 2 on the aromatic ring. As can be seen from the results reported in Table 1, entries 6 and 7, high yields of the corresponding benzothiophene-3-carboxylates were obtained when R 1 was an aryl group para-substituted with either an electron-releasing group (such as a methyl; yield of 2b, 76%) or an electron-withdrawing halogen atom (such as bromine; yield of 2c, 83%). A heteroaryl substituent such as 3thienyl was also compatible with reaction conditions, with formation of methyl 2-(thiophen-3-yl)benzo [b]thiophene-3carboxylate 2d in 70% yield (Table 1, entry 8), as well as an alkenyl group, such as 1-cyclohexenyl (yield of 2e, 79%, Table  1, entry 9). The process also worked nicely when R 1 was a simple alkyl group (such as butyl; yield of 2f, 83%, Table 1, entry 10), phenethyl (yield of 2g, 63%; Table 1, entry 11) and even a sterically demanding group, such as tert-butyl, with an acceptable yield of methyl 2-(tert-butyl)benzo [b]thiophene-3carboxylate 2h of 57% (Table 1, entry 12). Good yields of the corresponding benzothiophene-3-carboxylic esters 2i−k (61− 74%) were also achieved when the aromatic ring of the substrate bore either an electron-donating (such as Me, substrate 1i; Table 1, entry 13) or an electron-withdrawing group (such as F, substrates 1j and 1k; Table 1, entries 14 and 15).
To test the possibility to recycle the catalyst, we also performed the reaction of the parent substrate 1a in an ionic liquid as the solvent, such as 1-butyl-3-methylimidazolium tetrafluoroborate (BmimBF 4 ) in which the PdI 2 /KI system is perfectly soluble. 9 The methoxycarbonylation of 1a, carried out in a 3:1 mixture of BmimBF 4 -MeOH under the same conditions already optimized in MeOH, led to the formation of benzothiophene 2a in 40% yield at 75% substrate conversion. Complete conversion of 1a, with a good yield of 2a (68%), could be obtained working at 100°C under more concentrated conditions (0.05 rather than 0.02 mmol of 1a per mL of solvent) for 36 h (Table S2, entry 1, run 1, Supporting Information). Recycling experiments showed that no appreciable loss of catalytic activity occurred even after the fifth    (Table S2, entry 1, runs 2−6). Similar results were obtained with the other substrates tested, 1b, 1d, and 1g, as shown in Table S2, entries 2−4.
In conclusion, we have found that PdI 2 in conjunction with an excess of KI is able to catalyze the oxidative alkoxycarbonylation of readily available 2-(methylthio)phenylacetylenes under aerobic conditions (with O 2 from air as the external oxidant) to give high-value-added benzothiophene-3-carboxyxlic esters in a selective manner. The process takes place by intramolecular S-5-endo-dig cyclization followed by iodide-promoted S-demethylation, alkoxycarbonylation, and Pd(0) reoxidation to close the catalytic cycle. The catalytic system can be also conveniently recycled without appreciable loss of activity working in BmimBF 4 as the solvent. Our method thus provides a convenient direct catalytic approach to an important class of heterocyclic derivatives in one step and in a multicomponent fashion, starting from very simple building blocks (the acyclic organic substrate, CO, an alcohol, and O 2 ). ■ EXPERIMENTAL SECTION General Experimental Methods. Solvent and chemicals were reagent grade and were used without further purification. All reactions were analyzed by TLC on silica gel 60 F254 and by GLC using capillary columns with polymethylsilicone + 5% phenylsilicone as the stationary phase. Column chromatography was performed on silica gel 60 (70−230 mesh). Evaporation refers to the removal of solvent under reduced pressure. Melting points are uncorrected. 1 H NMR and 13 C{ 1 H}NMR spectra were recorded at 25°C on a 300 or 500 MHz spectrometer in CDCl 3 as the solvent and with Me 4 Si as internal standard. Chemical shifts (δ) and coupling constants (J) are given in ppm and in hertz (Hz), respectively. IR spectra were taken with an FT-IR spectrometer. Mass spectra were obtained using a GC-MS apparatus at 70 eV ionization voltage (normal resolution) and by electrospray ionization mass spectrometry (ESI-MS) (high resolution) with a UHD accurate-mass Q-TOF spectrometer equipped with a Dual AJS ESI source working in positive mode and were recorded in the 150−1000 m/z range. The LC-MS experimental conditions were as follows: N 2 was employed as desolvation gas at 300°C and a flow rate of 9 L/min. The nebulizer was set to 45 psig. The Sheat gas temperature was set at 350°C and a flow of 12 L/min. A potential of 3.5 kV was used on the capillary for positive ion mode. The fragmentor was set to 175 V.
General Procedure for the Synthesis of Benzo [b]thiophen-3-carboxylic Esters 2a, 2b, 2d, and 2g in BmimBF 4 (Table S2, Supporting Information). A 250 mL stainless-steel autoclave was charged in the presence of air with PdI 2 (5.4 mg, 0.015 mmol), KI (125 mg, 0.75 mmol), a solution of substrate 1 (0.30 mmol; 1a, 67.4 mg; 1b, 71.5 mg; 1d, 69.0 mg; 1g, 75.6 mg) in MeOH (1.5 mL), and BmimBF 4 (4.5 mL). The autoclave was sealed and, while the mixture was stirred, the autoclave was pressurized with CO (32 atm) and air (up to 40 atm). After being stirred at 100°C (jacketed autoclave with circulating thermic fluid) for 36 h, the autoclave was cooled, degassed, and opened. The mixture was then extracted with Et 2 O (6 × 10 mL), and the residue (still containing the catalyst dissolved in the ionic liquid) was used as such for the next recycle (see below). The collected ethereal phases were concentrated, and the product was purified by column chromatography on silica gel using as eluent hexane to hexane−AcOEt 95:5 to give pure benzo [b]thiophen-3carboxylic esters 2a, 2b, 2d, and 2g. The isolated yields obtained in each experiment are given in Table S2 (Supporting Information).
Catalyst Recycling Procedure. After removal of Et 2 O under vacuum, the residue obtained as described above, still containing the catalyst dissolved in the ionic liquid, was transferred into the autoclave. A solution of 1 (0.30 mmol) in MeOH (1.5 mL) was added, and then the same procedure described above was followed.